1. Field of the Invention
The present invention relates to an aminoalcohol derivative which is a ceramide analogue and a medicament, particularly an agent for treating neuronal diseases and an agent for protecting brain, comprising the same.
2. Brief Description of the Background Art
Glycosphingolipids (hereinafter referred to as xe2x80x9cGSLxe2x80x9d) are present as a constitutional component of cell surface membranes of mammalian cells and play important roles in cellular functions, such as development, growth, differentiation, malignant transformation, immunoreaction and the like, through a receptor function of a physiologically active substance, an intercellular mutual recognizing function, an intercellular interaction, and the like.
Among them, a ganglioside is a GSL containing sialic acid and is said to be active in the recovery from neuronal diseases, such as peripheral nervous injury, central nervous disorder and the like, i.e., an acceleration of nervous regeneration and a process of neurotransmission. Heretofore, the effectiveness of exogenous gangliosides has been investigated toward various pathological models of nervous system. As a medicament utilizing the same, a medicament named xe2x80x9cCronassial(trademark)xe2x80x9d has already been commercialized in Italy and a related patent is also known (JP-B-62-50450).
Currently, the addition of a ganglioside to an experimental system from outside is the most popular type of a procedure for searching a function of the ganglioside. In that case, however, a relation to endogenous gangliosides becomes a problem. That is, it is considered that the result obtained from the further addition of the ganglioside to the system where endogenous gangliosides present in cell membranes have already formed complexes with various cell surface receptors etc. does not always reflect the actual cytophysiological significance of endogenous gangliosides. Therefore, a method of specifically changing biosynthesis of endogenous GSLs is necessary to identify an intrinsic role of a ganglioside in cell cytophysiology.
Incidentally, it is reported that a ceramide analogue, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) specifically inhibits an enzyme for glucosylceramide biosynthesis and remarkably reduces intracellular content of all GSLs which are produced starting with glucosylceramide (J. Lipid Res., 28: 565-571 (1987)). Furthermore, it is also reported that D-threo-PDMP suppresses the extension of neurite (J. Biochem., 110: 96-103 (1991)). In addition, it has been found that D-threo-PDMP suppresses synaptic function and the suppression is specifically released by GQ1b among various gangliosides (Biochem. Biophys. Res. Commun., 222: 494-498 (1996)). Based on these results, it is suggested that the ganglioside GQ1b is an active molecule necessary for synaptic function and the importance of endogangliosides on nervous functions is recognized.
On the other hand, there is suggested a possibility that L-threo-PDMP (hereinafter often referred to as xe2x80x9cL-PDMPxe2x80x9d) which is an optical enantiomer of D-threo-PDMP accelerates the biosynthesis of GSL (J. Cell. Physiol., 141: 573-583 (1989)).
In addition, it is also shown that 2-acylaminopropanol compounds, such as L-threo-PDMP and the like, accelerate ganglioside biosynthesis of neurocytes and exhibit an effect of accelerating neurite extension (J. Neurochem., 67: 1821-1830, 1996) and an effect of accelerating synapse formation, and therefore, is promising as an agent for treating neuronal diseases (WO 95/05177).
Furthermore, as a result of the examination of the effects of L-threo-PDMP on MAPkinase (mitogen-activated protein kinase) activated when synaptic transmission is continuously accelerated by N-methyl-D-aspartate (NMDA) or a brain derived neurotropic factor (BDNF) in order to elucidate an action mechanism of the neurotropic factor-like activity of L-threo-PDMP, it was found that L-threo-PDMP activates MAPkinase for a long period of time in proportion to the effect of accelerating synapse formation and further, L-threo-PDMP increases the activity of an enzyme for GQ1b synthesis (Biochem. Biophys. Res. Commun., 237: 595-600 (1997)).
However, in order to exhibit the pharmaceutical effect of L-threo-PDMP in vivo, it is judged that there is room for the improvement in an pharmaceutical effect-toxicity ratio and a distribution ability of the compound into tissues.
An object of the present invention is to provide an aminoalcohol derivative or pharmaceutically acceptable salt thereof which has an activity of accelerating synapse formation and/or an activity of accelerating glycolipid biosynthesis, a low toxicity, and an improved distribution ability into tissues.
Another object of the present invention is to provide a medicament, particularly an agent for treating neuronal diseases or an agent for protecting brain comprising the aminoalcohol derivative.
The present invention have been achieved by an aminoalcohol derivative which is a ceramide analogue, and a medicament, especially an agent for treating neuronal diseases and an agent for protecting brain, comprising the same.
A first embodiment of the present invention is as follows:
(1) An aminoalcohol derivative represented by formula (I): 
wherein * represents an asymmetric carbon; and
R represents a residue of a monocarboxylic acid derivative represented by the following (i) or (ii), or a residue of a dicarboxylic acid or a derivative thereof represented by the following (iii):
(i) a residue of glycine or polyglycine represented by (COCH2NH)mZ,
wherein m represents an integer of from 1 to 3; and
Z represents an amino-protecting group or an alkanoyl group;
(ii) a residue of a carboxylic acid derivative represented by COxe2x80x94Wxe2x80x94Y,
wherein W represents an alkylene group or a cycloalkylene group; and
Y represents a hydroxyl group, a monosaccharide residue, an aryl group which is optionally substituted, or an alkoxyl group optionally having an oxygen atom in the alkyl chain;
(iii) a residue of a dicarboxylic acid or a derivative thereof represented by COxe2x80x94Wxe2x80x94COxe2x80x94X,
wherein W represents an alkylene group or a cycloalkylene group; and
X represents a hydroxyl group, a chain or cyclic alkoxyl group, an alkyl group, an xcex1-amino acid residue, or NR1R2, in which R1 and R2 are the same or different and each independently represents a hydrogen atom, a chain or cyclic alkyl group optionally having an oxygen atom in the alkyl chain, or a chain or cyclic hydroxyalkyl group optionally having an oxygen atom in the alkyl chain, or
a pharmaceutically acceptable salt thereof.
A second embodiment of the present invention is as follows:
(2) A medicament comprising, as an active ingredient, the aminoalcohol derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
Also, the compound of formula (I) has 4 configurations, (1S,2S), (1S,2R), (1R,2S), and (1R,2R). As the active ingredient of an agent for treating neuronal diseases and an agent for protecting brain, L-threo compound having a configuration of (1S,2S) is preferred.
Specific embodiments of the present invention include the following aminoalcohol derivatives and pharmaceutically acceptable salts thereof:
(a) The aminoalcohol derivative according to the above (1), wherein R is represented by any one of the following (i) to (iii) in formula (I):
(i) (COCH2NH)mZ,
wherein Z represents an amino-protecting group selected from an aralkyloxycarbonyl group having from 8 to 15 carbon atoms and an alkoxycarbonyl group having from 5 to 7 carbon atoms, or an alkanoyl group having from 4 to 8 carbon atoms;
(ii) COxe2x80x94Wxe2x80x94Y,
wherein W represents an alkylene group having from 1 to 12 carbon atoms or a cycloalkylene group having from 4 to 8 carbon atoms; and
Y represents a hydroxyl group, a glucose residue, a galactose residue, an N-acetylglucosamine residue, an N-acetylgalactosamine residue, a mannose residue, a fucose residue, a sialic acid residue, a phenyl group which is optionally substituted, an alkoxyl group having from 1 to 6 carbon atoms, or an alkoxyl group having from 4 to 12 carbon atoms having from 1 to 3 oxygen atoms in the alkyl chain;
COxe2x80x94Wxe2x80x94COxe2x80x94X,
wherein W represents an alkylene group having from 1 to 12 carbon atoms or a cycloalkylene group having from 4 to 8 carbon atoms; and
X represents a hydroxyl group, an alkoxyl group having from 1 to 8 carbon atoms, a cycloalkoxyl group having from 5 to 8 carbon atoms, an alkyl group having from 1 to 6 carbon atoms, a residue of an xcex1-amino acid having a reactive functional group in the side chain, or NR1R2, in which R1 and R2 are the same or different and each independently represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, cyclohexyl group or a hydroxyalkyl group having from 2 to 4 carbon atoms, or
a pharmaceutically acceptable salt thereof.
(b) The aminoalcohol derivative according to the above (1), wherein R is represented by any one of the following (i) to (iii) in formula (I):
(i) (COCH2NH)mZ,
wherein Z represents a benzyloxycarbonyl group, a t-butoxycarbonyl group, or a hexanoyl group;
(ii) COxe2x80x94Wxe2x80x94Y,
wherein W represents an alkylene group having from 1 to 9 carbon atoms; and
Y represents a hydroxyl group, a glucose residue, a galactose residue, an N-acetylglucosamine residue, an N-acetylgalactosamine residue, a sialic acid residue, a phenyl group which is substituted with an alkoxyl group having from 1 to 3 carbon atoms, an alkoxyl group having from 1 to 4 carbon atoms, or an alkoxyl group having from 6 to 8 carbon atoms having an oxygen atom in the alkyl chain;
(iii) COxe2x80x94Wxe2x80x94COxe2x80x94X,
wherein W represents an alkylene group having from 2 to 8 carbon atoms or a cyclohexylene group; and
X represents a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, a cyclohexyloxy group, a methyl group, a residue of an amino acid selected from lysine, arginine, histidine, aspartic acid, glutamic acid, ornithine, cysteine, serine, threonine and tyrosine, or NR1R2, in which R1 and R2 are the same or different and each independently represents a hydrogen atom, a straight chain alkyl group having from 1 to 6 carbon atoms, a cyclohexyl group, or a hydroxyethyl group, or
a pharmaceutically acceptable salt thereof.
(c) The aminoalcohol derivative according to the above (1), wherein, in formula (I), R is represented by COxe2x80x94Wxe2x80x94COxe2x80x94X, in which W represents an alkylene group having from 2 to 8 carbon atoms; and X represents a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, or a methyl group, or a pharmaceutically acceptable salt thereof.
(d) The aminoalcohol derivative according to the above (1), wherein, in formula (I), R is represented by COxe2x80x94Wxe2x80x94COxe2x80x94X, in which W represents an alkylene group having from 4 to 8 carbon atoms; and X represents a lysine residue or an ornithine residue, or a pharmaceutically acceptable salt thereof.
(e) The aminoalcohol derivative according to the above (1), wherein, in formula (I), R is represented by COxe2x80x94Wxe2x80x94COxe2x80x94X, in which W represents an alkylene group having from 4 to 8 carbon atoms or cyclohexylene group; and X represents NR1R2, in which R1 and R2 are the same or different and each independently represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an n-butyl group, an n-hexyl group, a cyclohexyl group, or a hydroxyethyl group, or a pharmaceutically acceptable salt thereof.
(f) The aminoalcohol derivative according to the above (1), wherein, in formula (I), R is represented by COxe2x80x94Wxe2x80x94Y, in which W represents a nonylene group; and Y represents a hydroxyl group, or a pharmaceutically acceptable salt thereof.
(g) The aminoalcohol derivative according to the above (1), wherein, in formula (I), R is represented by COxe2x80x94Wxe2x80x94Y, in which W represents a methylene group; and Y represents an n-butoxy group or an alkoxyl group having from 6 to 8 carbon atoms having an oxygen atom in the alkyl chain, or a pharmaceutically acceptable salt thereof.
(h) The aminoalcohol derivative according to the above (1), wherein, in formula (I), R is represented by COxe2x80x94Wxe2x80x94Y, in which W represents an octylene group; and Y represents a sialic acid residue, or a pharmaceutically acceptable salt thereof.
Furthermore, embodiments of suitable medicaments of the present invention include an agent for treating neuronal diseases and an agent for protecting brain, comprising, as an active ingredient, the aminoalcohol derivative described in any one of the above (1) and (a) to (h) or a pharmaceutically acceptable salt thereof.
The present inventors have found that the modification of an acylamino group of a 2-acylaminopropanol compound, such as L-threo-PDMP or the like, lowers the toxicity of the compound and remarkably improves a distribution ability of the compound into tissues when the compound is administered to a mammal, and have accomplished the present invention based on these findings.
The compound of the present invention is an aminoalcohol derivative represented by formula (I) or a pharmaceutically acceptable salt thereof (hereinafter often referred to as xe2x80x9cthe compound of the present inventionxe2x80x9d), and the definitions (i) to (iii) of substituent R in the formula are as described above. Specific examples corresponding to the definitions (i) to (iii) are shown below.
Examples of the compound of the present invention represented by formula (I) wherein R is (COCH2NH)mZ include aminoalcohol derivatives, wherein m represents an integer of from 1 to 3, preferably 1 or 2; and Z represents an amino-protecting group selected from an aralkyloxycarbonyl group having from 8 to 15 carbon atoms and an alkoxycarbonyl group having from 5 to 7 carbon atoms, or an alkanoyl group having from 4 to 8 carbon atoms, or pharmaceutically acceptable salts thereof.
The amino-protecting group includes urethane-type protecting groups. Examples include a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-bromobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group, a p-phenylazobenzyloxycarbonyl group, a t-butoxycarbonyl group, and a cyclopentyloxycarbonyl group. Among these, a benzyloxycarbonyl group and a t-butoxycarbonyl group are preferred. The alkanoyl group is preferably a hexanoyl group.
Specific examples of the compounds represented by formula (I) wherein R is (COCH2NH)mZ include:
(1S,2S)-2-benzyloxycarbonylglycylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-benzyloxycarbonylglycylglycylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(n-butoxy)carbonylglycylamino-3-morpholino-1-phenyl-1-propanol, and
(1S,2S)-2-(n-hexanoyl)glycylamino-3-morpholino-1-phenyl-1-propanol.
Examples of the compound of the present invention represented by formula (I) wherein R is COxe2x80x94Wxe2x80x94COxe2x80x94X include aminoalcohol derivatives, wherein W represents an alkylene group having from 1 to 12 carbon atoms or a cycloalkylene group having from 4 to 8 carbon atoms; and X represents a hydroxyl group, an alkoxyl group having from 1 to 8 carbon atoms, a cycloalkoxyl group having from 5 to 8 carbon atoms, an alkyl group having from 1 to 6 carbon atoms, a residue of an xcex1-amino acid having a reactive functional group (e.g., amino group, guanidino group, carboxyl group, or hydroxyl group) in the side chain, or NR1R2 (in which R1 and R2 are the same or different and each independently represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cyclohexyl group, or a hydroxyalkyl group having from 2 to 4 carbon atoms), or pharmaceutically acceptable salts thereof. Specific examples include compounds, wherein W represents an alkylene group having from 2 to 8 carbon atoms or a cyclohexylene group; and X represents a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, a cyclohexyloxy group; methyl group, a residue of an xcex1-amino acid selected from lysine, arginine, histidine, aspartic acid, glutamic acid, ornithine, cysteine, serine, threonine and tyrosine, or NR1R2 (in which R1 and R2 are the same or different and each independently represents a hydrogen atom, a straight chain alkyl group having from 1 to 6 carbon atoms, a cyclohexyl group, or a hydroxyethyl group).
More specific examples of the compound represented by formula (I) wherein R is COxe2x80x94Wxe2x80x94COxe2x80x94X include:
(1S,2S)-2-(n-butoxy)butanedioylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-ethoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-isopropoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(n-butoxyhexanedioyl)amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-methoxydecanedioylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(9-carboxynonanoyl)amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(7-oxooctanoyl)amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S,12S)-2-(12-amino-7-aza-6-oxo-12-carboxydodecanoyl)amino-3-morpholino-1-phenyl-1-propanol, and
(1S,2S,16S)-2-(16-amino-11-aza-10-oxo-16-carboxyhexadecanoyl)amino-3-morpholino-1-phenyl-1-propanol.
In addition, examples also include:
(1S,2S)-2-(3-butylcarbamoyl)propionylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(N-butyl-N-methylamino)butanedioylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(5-ethylcarbamoyl)pentanoylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(5-cyclohexylcarbamoyl)pentanoylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(5-hexylcarbamoyl)pentanoylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(9-butylcarbamoyl)nonanoylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(9-hexylcarbamoyl)nonanoylamino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(N,N-diethanolamino)decanedioylamino-3-morpholino-1-phenyl-1-propanol, and
(1S,2S)-2-(cyclohexane-4-hexylcarbamoyl-1-carbonyl)amino-3-morpholino-1-phenyl-1-propanol.
Furthermore, examples of the compound of the present invention wherein R is COxe2x80x94Wxe2x80x94Y in formula (I) include aminoalcohol derivatives, wherein W represents an alkylene group having from 1 to 12 carbon atoms or a cycloalkylene group having from 4 to 8 carbon atoms; and Y represents a hydroxyl group, a glucose residue, a galactose residue, an N-acetylglucosamine residue, an N-acetylgalactosamine residue, a mannose residue, a fucose residue, a sialic acid residue, a phenyl group which is optionally substituted, an alkoxyl group having from 1 to 6 carbon atoms, or an alkoxyl group having from 4 to 12 carbon atoms having from 1 to 3 oxygen atoms in the alkyl chain, or a pharmaceutically acceptable salt thereof. Specific examples include compounds, wherein W represents an alkylene group having from 1 to 9 carbon atoms; and Y represents a hydroxyl group, a glucose residue, a galactose residue, an N-acetylglucosamine residue, an N-acetylgalactosamine residue, a sialic acid residue, a phenyl group which is substituted with an alkoxyl group having from 1 to 3 carbon atoms, an alkoxyl group having from 1 to 4 carbon atoms or an alkoxyl group having from 6 to 8 carbon atoms having an oxygen atom in the alkyl chain.
More specific examples of the compound represented by formula (I) wherein R is COxe2x80x94Wxe2x80x94Y include:
(1S,2S)-2-(10-hydroxydecanoyl)amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(9-sialylnonanoyl)amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-[4-(4-methoxyphenyl)butyryl]amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(3-oxaheptanoyl)amino-3-morpholino-1-phenyl-1-propanol,
(1S,2S)-2-(3,6-dioxadecanoyl)amino-3-morpholino-1-phenyl-1-propanol, and
(1S,2S)-2-(3,6-dioxadodecanoyl)amino-3-morpholino-1-phenyl-1-propanol.
Among the compounds of the present invention, the particular examples of the compounds having a low toxicity and a high activity of synapse formation are especially the compounds wherein R is represented by COxe2x80x94Wxe2x80x94COxe2x80x94X or the compounds wherein R is represented by COxe2x80x94Wxe2x80x94Y, in which W and X or Y are represented by the following combinations shown in Table 1.
The aminoalcohol derivative of the present invention is obtained by introducing the substituent R to an amino group of an aminoalcohol derivative represented by formula (II) through a peptide bond-forming reaction which itself is already known in the art using a carboxylic acid corresponding to R or its reactive derivative, but the preparation of the compounds is not limited to such a method. 
When the carboxylic acid compound corresponding to R contains a highly reactive functional group, the functional group can be protected with an appropriate protecting group in advance and, after a desired peptide bond-forming reaction, the protecting group can be removed. Furthermore, the desired compound can be obtained by subjecting repeatedly the reactive functional group (e.g., amino group or carboxyl group) to a peptide bond-forming reaction or esterifying reaction which itself is already known in the art.
Examples of the peptide bond-forming method include a method using a carboxylic acid corresponding to the above R and a condensing agent, a method using an acid anhydride, and a method using an acid halide.
Specifically, examples include a method of reacting an aminoalcohol derivative represented by formula (II) or acid adduct salt thereof (e.g., hydrochloride) with the carboxylic acid and a condensing agent (e.g., dicyclohexylcarbodiimide (DCC) or water soluble carbodiimide (WSC), more specifically 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)) in a solvent such as water, methylene chloride, pyridine or ethanol using, if necessary, an activating agent such as N-hydroxysuccinimide; and a method of reacting the same using an acid anhydride or acid halide (e.g., acid chloride) and a base (e.g., an organic base such as pyridine, triethylamine, diisopropylethylamine or N-methylmorpholine, or an inorganic base such as sodium hydrogen carbonate). The solvent to be used in the reaction is not particularly limited unless it inhibits the peptide bond-forming reaction provided that it dissolves the aminoalcohol derivative and the carboxylic acid compound.
The peptide bond-forming reaction is carried out usually at about 0 to 50xc2x0 C., preferably at room temperature (5 to 35xc2x0 C. (JIS K0050)) for several hours to several days, preferably 10 hours to 2 days, but the reaction conditions can be suitably determined by those skilled in the art through a preliminary experiment.
After the peptide bond-forming reaction, the compound of the present invention represented by formula (I) can be purified and isolated by suitably combining purifying means which themselves are known, for example, an extraction with a solvent, such as ethyl acetate, chloroform or the like, various types of chromatography (adsorption chromatography, ion exchange chromatography, etc.), and crystallization.
As the method for producing the compound of formula (II) which is a starting material for the compound of the present invention, the known method described in JP-A-9-216856 can be optionally adopted. Concretely, the compound is obtained as the compound having a desired stereochemical configuration through successive reaction according to the reaction scheme shown in the following by use of a chiral compound represented by formula (III) as the starting material. 
wherein * represents an asymmetric carbon; P1 represents an amino-protecting group (e.g., benzyloxycarbonyl group, t-butoxycarbonyl group, benzenesulfonyl group, or fluorenylmethoxycarbonyl group); and Y represents a leaving group (e.g., methanesulfonyl group, trihalogenomethanesulfonyl group, p-toluenesulfonyl group, benzenesulfonyl group, or p-bromobenzenesulfonyl group)
Namely, a leaving group (Y) is introduced only to the primary hydroxyl group of the aminoalcohol derivative represented by formula (III) to form a compound represented by formula (IV) and then, the resulting compound is reacted with morpholine to form an aminoalcohol derivative represented by formula (V). A chiral aminoalcohol derivative represented by formula (II) is finally obtainable by removing P1 from the compound.
The compound of formula (II) thus obtained is converted into the compound of formula (I) according to the above-described reaction.
The pharmaceutically acceptable salt of the compound of the present invention represented by formula (I) include salts with an inorganic acid, such as hydrochloric acid, phosphoric acid, sulfuric acid or nitric acid; and salts of an organic acid, such as formic acid, acetic acid, citric acid, lactic acid, malic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, trifluoroacetic acid, methanesulfonic acid (mesylic acid), p-toluenesulfonic acid (tosylic acid) or the like. The salts can be produced according to an itself known method, and, for example, is produced by dissolving a compound (free-type) represented by formula (I) into a suitable solvent, such as alcohol or the like, adding usually equimolar amount of the above acid to react them, and then optionally evaporating the solvent.
The aminoalcohol derivative represented by formula (I) or pharmaceutically acceptable salt thereof which is the compound of the present invention has a property participating the action of controlling glycolipid biosynthesis and thus has utility as a medicament based on the property.
Among the compounds represented by formula (I), the compounds having an effect of accelerating synapse formation and/or an action of accelerating glycolipid (ganglioside etc.) biosynthesis are expected to have an effect of accelerating neurite extension, an effect of preventing neurocyte death, and an effect of activating MAPkinase, and therefore useful as an agent for treating neuronal diseases, based on such effects. Accordingly, by administering an effective amount of the compound of the present invention to mammals including human which suffer from neuronal diseases caused by disorders of peripheral nervous system or central nervous system, the animals can be treated. Examples of representative diseases include various diseases of central nervous system which are expected to be treated by regenerating nerve fibers, for example, stroke, cerebral infarction, sequelae of cerebrovascular accident, cerebral hemorrhage, cerebral injury, dysmnesia, senile dementia, Alzheimer""s disease and Parkinson""s disease; and various diseases of peripheral nervous system, for example, polyneuropathy caused by cacochymia, mechanical neuropathy and toxic neuropathy. In particular, the compound of the present invention having an activity of accelerating synapse formation is effective as an agent for treating diseases of central nervous system, particularly an agent for protecting brain or an agent for potentiating and protecting cerebral nerves, for example, for treating sequelae of cerebrovascular accident.
Formulation of Pharmaceutical Preparation
The compound of the present invention represented by formula (I) or pharmaceutically acceptable salt thereof can be used for treating various diseases (e.g., neuronal diseases) of mammals including human and a pharmaceutical preparation to be administered orally or parenterally can be obtained by using the compound or the salt with a carrier, an excipient, and other additives.
Examples of the oral preparation include solid preparations (e.g., powder, granule, capsule, tablet, etc.); and liquid preparations (e.g., syrup, elixir, emulsion, etc.). The powder can be obtained by, for example, mixing with an excipient, such as lactose, starch, crystalline cellulose, calcium lactate, calcium hydrogen phosphate, magnesium aluminometasilicate, silicic acid anhydride or the like. The granule can be obtained by adding the above excipient and, if necessary, for example, a binder, such as sucrose, hydroxypropyl cellulose, polyvinylpyrrolidone or the like, or a disintegrator, such as carboxymethyl cellulose, calcium carboxymethyl cellulose or the like, and granulating the mixture according to a wet method or a dry method. The tablet can be obtained by tableting the above powder or granule as such or with a lubricant, such as magnesium stearate, talc or the like. Furthermore, the above tablet or granule can be made an enteric or sustained action preparation by coating it with an enteric base, such as hydroxypropylmethyl cellulose phthalate, a methyl methacrylate copolymer, hydroxypropylmethyl cellulose acetate, hydroxypropylmethyl cellulose succinate or the like, or coating it with ethyl cellulose, carnauba wax, hardened oil, white shellac etc.
A hard capsule can be obtained by filling a hard capsule with the above powder or granule. Furthermore, a soft capsule can be obtained by dissolving the compound of the present invention in glycerin, polyethylene glycol, sesame oil, olive oil, etc. and covering the solution with a gelatin film.
The syrup can be obtained by dissolving a sweetener, such as sucrose, sorbitol, glycerin or the like, and the compound of the present invention in water. In addition to the sweetener and water, essential oil, ethanol and the like can be added to prepare an elixir, or gum arabic, tragacanth, a polysorbate (polysorbate 20, polysorbate 60, polysorbate 80 (Tween 80)), sodium carboxymethyl cellulose and the like can be added to prepare an emulsion or a suspension. Furthermore, a corrective, a coloring agent, a preservative and the like can be added to these liquid preparations, if necessary.
Examples of the parenteral preparation include injections, intrarectal preparations, pessary, endermic preparations, inhalants, aerosol, ophthalmic preparations, and the like. The injection can be obtained by adding a nonionic surfactant, such as a polysorbate or the like, if necessary; a pH-adjusting agent, such as hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium monohydrogen phosphate, sodium dihydrogen phosphate or the like; an isotonizing agent, such as sodium chloride, glucose or the like; an stabilizing agent, such as an amino acid or the like; and distilled water for injection or physiological saline to the compound of the present invention, sterilizing and filtering the mixture, and then filling an ampoule with the mixture. Further, an injection which is to be dissolved when it is used can be obtained by adding mannitol, dextran, gelatin and the like, and lyophilizing the mixture under vacuum. Alternatively, a powder-filled injection can be made. Also, an emulsion for injection can be made by adding an emulsifier such as lecithin, a polysorbate, polyoxyethylene hardened castor oil, macrogol or the like to the compound of the present invention and then emulsifying the mixture in water.
Furthermore, examples of the injection include liposome preparations and lipid microspheres which enable the improvements of solubility and a migration rate to a target organ. In particular, nanosphere-liposome (lipid ultrafine particle) can not only increase a concentration in blood without being taken into reticuloendothelial tissues and lower a minimum effective dose required for exhibiting a pharmaceutical effect, but also pass a blood-brain barrier by about 10 times easier, so that it is suitable when it is used for treating cerebral neuronal diseases. The liposome preparation can be prepared according to a known liposome preparation method (C. G. Knight, Liposomes: From Physical Structure to Therapeutic Applications, pp. 51-82, Elsevier, Amsterdam (1981); Proc. Natl. Acad. Sci., USA, 75: 4194 (1978)).
That is, examples of an amphipathic substance forming a liposome membrane include phospholipids, such as natural phospholipids (e.g., yolk lecithin, soybean lecithin, sphingomyelin, phosphatidyl serine, phosphatidyl glycerol, phosphatidyl inositol, diphosphatidyl glycerol, phosphatidyl ethanolamine, cardiolipin, etc.), synthetic phospholipids (e.g., distearoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, dipalmitoyl phosphatidyl ethanolamine, etc.) or the like. Furthermore, in order to improve membrane stability, fluidity and membrane permeability of the medicament, known various additives can be added. Examples include cholesterols (e.g., cholesterol, ergosterol, phytosterol, sitosterol, stigmasterol, etc.), substances which are known to impart negative charge to liposome (e.g., phosphatidic acid, dicetyl phosphate, etc.), substances which are known to impart positive charge (e.g., stearylamine, stearylamine acetate, etc.), antioxidants (e.g., tocopherol, etc.), oily substances (e.g., soybean oil, cottonseed oil, sesame oil, liver oil, etc.) and the like.
Preparation of liposome can be carried out according to, for example, the following method. The above amphipathic substance, additives and the compound of the present invention are dissolved in an organic solvent (e.g., single solvent, such as chloroform, dichloromethane, ethanol, methanol, hexane or the like, or a mixed solvent thereof) respectively, both solutions are mixed, the organic solvent is removed in a vessel, such as a flask or the like, in the presence of an inert gas (e.g., nitrogen gas, argon gas, etc.), and a thin membrane is attached to the wall of the vessel. Then, this thin membrane is added to a suitable aqueous medium (e.g., physiological saline, a buffer, a phosphate buffered physiological saline, etc.), and the mixture was stirred by means of a stirrer. In order to obtain liposome having a small particle size, the mixture was further dispersed by use of an ultrasonic emulsifier, a pressurization type emulsifier, a French press cell pulverizer or the like. As described above, preparation of liposome proceeds by treating, with a membrane filter, a liquid in which the amphipathic substance and the like required for preparation of liposome and the compound of the present invention are dispersed in the aqueous medium to obtain nanosphere-liposome (lipid ultrafine particle; a particle size of about 25 to 50 nm) in which a particle size distribution is controlled. Furthermore, liposome can be subjected to fractionation treatment, such as ultrafiltration, centrifugation, gel filtration or the like, to remove the medicament which is not supported.
Furthermore, the liposome can be made to pass a blood-brain barrier easily by supporting an aminoalcohol derivative of formula (I), the compound of the present invention on liposome having, on a membrane thereof, a glucose residue, a tyrosine residue, a mannose residue or sulfatide obtained by adding xcex2-octylglucoside, L-tyrosin-7-amido-4-methylcoumarin, phenylaminomannoside or sulfatide as a membrane-forming substance in addition to the above amphipathic substance and additives (as to a method itself, see JP-A-4-69332).
The lipid microsphere is obtained by dissolving the compound of the present invention in soybean oil, sesame oil or the like, stirring by means of a stirrer after the addition of a natural phospholipid, glycerin, water and the like, and further dispersing the mixture by use of an ultrasonic emulsifier, a pressurization type emulsifier, a French press cell pulverizer or the like.
The intrarectal preparation can be obtained by adding a base for a suppository such as mono-, di- or triglyceride of cacao fatty acid, polyethylene glycol or the like to the compound of the present invention, then melting the mixture by heating, pouring it into a mold and cooling it, or dissolving the compound of the present invention in polyethylene glycol, soybean oil or the like and then covering the mixture with a gelatin film.
The endermic preparation can be obtained by adding white petrolatum, beeswax, liquid paraffin, polyethylene glycol or the like to the compound of the present invention, heating the mixture, if necessary, and kneading it.
A tape preparation can be obtained by kneading the compound of the present invention with an adhesive, such as rosin, an alkyl acrylate polymer or the like, and spreading the mixture on non-woven fabric or the like.
The inhalation can be obtained by, for example, dissolving or dispersing the compound of the present invention in a propellant, such as a pharmaceutically acceptable inert gas or the like, and filling a pressure container with the mixture.
In the case that the compound of the present invention is used as an agent for treating neuronal diseases, particularly an agent for protecting brain or an agent for potentiating and protecting cranial nerves, an injection is preferable and an intravenous injection is more preferable. Such injections can be a lipid microsphere preparation or a preparation containing a surfactant in consideration of the distribution ability of the compound of the present invention to brain.
Method for Administration:
The method for administering a medicament containing the compound of the present invention as an active ingredient is not particularly limited, but when it is used for treating neuronal diseases caused by disorders of central nervous system, preferred is injection, such as intramuscular injection, intravenous injection, hypodermic injection, intraperitoneal injection or the like, intrarectal administration, intrapulmonary administration, ophthalmic administration, oral administration, or the like. Furthermore, when it is used for treating neuronal diseases caused by disorders of peripheral nervous system, preferred is intramuscular injection, endermic administration, ophthalmic administration, oral administration, or the like.
The dose can be suitably determined depending on age, health condition, body weight and the like of a patient, but the compound of the present invention is generally administered in an amount of 0.25 to 200 mg/kg, preferably 0.5 to 100 mg/kg by one dose or divided doses per day.
The aminoalcohol derivative represented by formula (I) or pharmaceutically acceptable salt thereof which is the compound of the present invention has a property participating the action of controlling glycolipid biosynthesis and thus has utility as a medicament based on the property, so that it is possible to provide an effective medicament containing the compound of the present invention. Among the compounds of the present invention, the compound having an effect of accelerating synapse formation and/or an action of accelerating glycolipid biosynthesis is especially expected to have an effect of accelerating nurite extension, an effect of preventing neurocyte death, and an effect of activating MAPkinase, and therefore promising as an agent for treating neuronal diseases. The compound is effective as an agent for treating diseases of central nervous system, particularly an agent for protecting brain or an agent for potentiating and protecting cranial nerves, for example, for the treatment of sequelae of cerebrovascular accident, and as an agent for treating diseases of peripheral nervous system, for example, for the treatment of polyneuropathy caused by cacochymia, mechanical neuropathy or toxic neuropathy.
The present invention will be explained in detail with reference to the examples, but the present invention is not limited thereto.